Our data indicate that pharmacological stimulation of group I metabotropic glutamate receptors (group I mGluRs) elicits irreversible epileptiform activity in the hippocampal slices via stimulation of mRNA translation and de novo protein synthesis. Our recent results suggest that the group I mGluR-stimulated mRNA translation, that underlies epileptogenesis, is normally repressed by the Fragile X mental retardation protein (FMRP). By restricting the translation process, FMRP serves as a safe-guard against the induction of group I mGluR-mediated epileptiform discharges in normal subjects. Fragile X Syndrome (FXS), the most common hereditary form of mental retardation, is caused by a loss of FMRP function. In vivo and in vitro experiments using the FXS model mouse show that the propensity for epileptogenesis, presumably mediated by group I mGluRs, is significantly enhanced. Seizure discharges elicited in FXS model mice are potently suppressed by group I mGluR antagonists. The findings in the FXS mouse model mirror the clinical condition, where FXS patients have increased likelihood of epilepsy compared to the general population. The overall goals of the proposed research are (A) to elucidate the molecular and cellular signaling mechanisms underlying epileptogenesis in the FXS mouse preparation and (B) to identify conditions under which group I mGluR activation can cause epileptogenesis in normal, wild type preparations. Electrophysiological, pharmacological, and biochemical techniques will be used to address three specific aims: (1) To assess the role of group I mGluRs in the synaptic induction of epileptiform discharges in the FXS mouse preparation;(2) To characterize the synaptic and cellular plasticity, elicited by the inducing synaptic stimulation, that is necessary for the maintenance of epileptiform discharges in the FXS mouse preparation;and (3) To define the signaling mechanisms through which epileptiform discharges are elicited in the wild type preparation by group I mGluR stimulation. The relevance of the group I mGluR model of epileptogenesis to epilepsy in Fragile X syndrome will be further explored. Results from the proposed study will provide fundamental information on the role of group I mGluRs in epileptogenesis. Such information will be useful in the design of rational therapeutic approaches to combat epilepsy, particularly in patients with Fragile X syndrome. PUBLIC HEALTH RELEVANCE This study examines how glutamate, the most prominent excitatory neurotransmitter in the brain, can cause epilepsy both in the general population and, in particular, in patients with Fragile X syndrome - Fragile X is the most common hereditary form of mental retardation. The proposed experiments will identify abnormal responses of nerve cells in the brain to glutamate and how these abnormal responses can ultimately cause epilepsy. It is expected that the results of the study will contribute towards the design of more specific drugs to combat epilepsy and improve treatment of patients with Fragile X syndrome.